US10709681B2 - Biologically active cannabidiol analogs - Google Patents

Biologically active cannabidiol analogs Download PDF

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US10709681B2
US10709681B2 US16/073,766 US201716073766A US10709681B2 US 10709681 B2 US10709681 B2 US 10709681B2 US 201716073766 A US201716073766 A US 201716073766A US 10709681 B2 US10709681 B2 US 10709681B2
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amino acid
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Mahmoud A. Elsohly
Soumyajit Majumdar
Waseem Gul
Mohammad Khalid Ashfaq
Kenneth Joseph Sufka
Hannah Marie Harris
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University of Mississippi
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Definitions

  • the present invention is directed to the development of biologically active cannabidiol analogs capable of being formulated into pharmaceutical compositions, and methods of using such compositions for a pharmacological benefit.
  • biologically active CBD analogs possessed analgesic properties alone and in combination of a sub-analgesic dose of morphine in cisplatin induced neuropathy. Furthermore, these analogs exhibited blocking properties to opiate addiction.
  • Cannabidiol has a variety of pharmacological benefits, including, but not limited to anti-inflammatory, analgesic, anti-convulsant, anti-psychotic, anti-fibrosis, anti-scarring, anti-oxidant, neuroprotective, anti-infective, anti-cancer and immunomodulatory effects.
  • Cisplatin is a common chemotherapy used to treat a variety of cancers. Unfortunately, cisplatin has a dose limiting effect wherein 50-85% of patients develop peripheral neuropathy 3-6 months into treatment. Cisplatin-induced neuropathy (CIN) presents in a “stocking and glove” distribution causing tingling paresthesia, numbness, and allodynia (Paice, 2010; Amptoulach et al., 2011). Pain management for CIN includes anticonvulsant, antidepressant, and non-steroidal anti-inflammatory drugs. These drugs prove to be well tolerated in patients but show little efficacy in treating CIN (Wolf et al., 2008; Amptoulach et al., 2011; Miltenburg et al., 2014).
  • opioids can provide effective CIN pain relief, 76-96% of patients report aversive side effects that include sedation, nausea, and fatigue which limit usefulness and diminish patient quality of life (Guindon et al., 2008; Toth & Au, 2008). Added concerns of opioid therapy include tolerance, dose escalation, and dependence that can lead to withdrawal symptoms upon CIN resolution (Kim et al., 2015). Collectively, these observations suggest a need to develop novel pharmacotherapies for CIN.
  • Cannabinoids are used in oncology settings to control nausea, weight loss, lack of appetite, and chemotherapy related pain (Alexander et al., 2009).
  • CB analgesia in both chronic and acute pain models is mediated through CB1 and CB2 receptors that are differentially expressed in the central and peripheral nervous systems (Chiou et al., 2013; Pisanti et al., 2013).
  • An emerging body of literature supports the notion that CB systems may also modulate CIN.
  • CB1 and CB2 direct and indirect agonists attenuate tactile allodynia in rodent models of CIN (Vera et al., 2013; Guindon et al., 2012, Khasabova et al., 2012).
  • CB compounds have modest efficacy and are of limited usefulness.
  • CB1 and opioid receptors are co-localized in pain pathways.
  • the CB1 agonist THC shows synergistic effects with sub-analgesic doses of the mu opioid agonist morphine in a rat arthritic pain model (Cox et al., 2007).
  • use of any CB1 agonist in oncology settings is unlikely due to these compounds increasing the proliferation and growth of some tumor cells (Hall et al., 2005).
  • CBD cannabidiol
  • Described herein are biologically active analogs of CBD that can be administered by a wide variety of routes of administration including but not limited to orally, transdermally or transmucosally (e.g. buccal, rectal, ocular, nasal) to a mammal, such as a human, for the treatment of a medical condition such as pain, inflammation, epilepsy and ocular diseases, including but not limited to treatment of diseases of the retina (e.g. diabetic retinopathy and macular degeneration).
  • routes of administration including but not limited to orally, transdermally or transmucosally (e.g. buccal, rectal, ocular, nasal) to a mammal, such as a human, for the treatment of a medical condition such as pain, inflammation, epilepsy and ocular diseases, including but not limited to treatment of diseases of the retina (e.g. diabetic retinopathy and macular degeneration).
  • CBD analogs containing a natural amino acid and a dicarboxylic acid moiety attached to one of the hydroxyl groups (with the amino acid linked to CBD through an ester linkage and the dicarboxylic acid attached to the amino group of the amino acid in an amide linkage) with the other hydroxyl group free, result in higher than expected concentrations in vivo. Furthermore, the amino acid esters of CBD (di esters) must be reacted with a dicarboxylic acid, forming amide linkages with the free amine group of the cannabidiol-amino acid ester, to affect bioavailability in vivo.
  • Exemplary CBD analogs can be represented by the following formulae:
  • CBD-divalinate-dihemisuccinate (1) CBD-mono-valinate-di-hemisuccinate (2) and CBD-monovalinate-hemisuccinate (3) are shown above.
  • This formula I shows the structure for amino acid ester and/or dicarboxylic acid ester analogs wherein R 1 or R 2 or both is/are the residue of a moiety formed by the reaction of the amino group of the amino acid ester with a dicarboxylic acid or a dicarboxylic acid derivative and R 1 or R 2 (in case of the mono amino acid ester) is the residue of a dicarboxylic acid or dicarboxylic acid derivative or a Hydrogen (H). Both R 1 and R 2 could be residues of moieties formed by reaction of the amine group of the amino acid ester at both sites with a dicarboxylic acid.
  • the biologically active analogs of the invention can be formed from amino acids including, for example, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoserine lactone, and norleucine.
  • a “dicarboxylic acid” herein is meant an organic acid that has two carboxyl groups (—COOH).
  • dicarboxylic acids can be written as HO 2 C—R—CO 2 H, where R can be straight chain or branched aliphatic or aromatic.
  • suitable dicarboxylic acids in this invention include, but are not limited to, malonic acid, malic acid, glutaric acid, succinic acid, and phthalic acid.
  • Dicarboxylic acids are reacted as their anhydrides and reactive derivatives of dicarboxylic acids such as, for example, dicarboxylic acid halides.
  • biologically active CBD analogs such as described above including, for example CBD-val-HS
  • CBD-val-HS possess several attributes that suggest that biologically active CBD analogs may be useful in pain management.
  • CBD-val-HS has much better absorption and a longer biological half-life than CBD.
  • CBD-val-HS is biologically active and fully efficacious as certain opioids in this CIN murine model.
  • the present invention comprises compounds of the formula I
  • R 1 or R 2 or both is/are the residue of a moiety formed by the reaction of an amino group of the amino acid ester of R 1 or R 2 or both with a dicarboxylic acid or a dicarboxylic acid derivative and the other R 1 or R 2 (in the case of the mono) is the residue of a dicarboxylic acid or dicarboxylic acid derivative or Hydrogen (H), (i.e. underivatized), and salts thereof.
  • H Hydrogen
  • the amino acid is can be, but not limited to the listed, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • the present invention still further comprises biologically active compounds of the formula II:
  • R′ 1 and R′ 2 or both are ester residue(s) of natural amino acids and derivatives thereof and salts thereof.
  • the amino acid ester(s) is (are) selected from but not limited to one of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine and derivatives thereof and salts thereof.
  • R 1 or R 2 or both is/are an amino acid ester residue of a moiety formed by the reaction of a carboxyl group of an amino acid with one or both phenolic groups of cannabidiol; or one of R 1 or R 2 or both is/are an ester residue of a moiety formed by the reaction of a carboxyl group of a dicarboxylic acid or dicarboxylic acid derivative with one or both phenolic groups of cannabidiol; or one of R 1 or R 2 is the amino acid ester residue of the reaction of the phenolic group of cannabidiol with the carboxyl group of an amino acid and the other R 1 or R 2 is the ester residue of the reaction of the phenolic group of cannabidiol with the carboxyl of a dicarboxylic acid or dicarboxylic acid derivative; or one of R 1 or R 2 (in the case of the mono) is hydrogen (H), (i.e. underivatized) and the other R 1 or R 2 is
  • R 1 and R 2 is/are an amino acid ester moiety which is further reacted with a dicarboxylic acid or dicarboxylic acid derivative to form an amide moiety by the reaction of the amino group of the amino acid ester with a carboxyl moiety of the dicarboxylic acid or dicarboxylic acid derivative.
  • the amino acid is any but not limited to one of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • R 1 or R 2 or both are ester residue(s) of natural amino acids and derivatives thereof and salts thereof.
  • Exemplary but not exclusive examples of the present invention include: the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate, CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate, CBD-Mono-Valinate-Mono-Hemisuccinate, or CBD-monovalinate-dihemisuccinate.
  • the present invention further encompasses a formulation for administration of a biologically active CBD analog for the treatment of a disease condition comprising a therapeutically effective amount of at least one compound of formula I, II or III in an acceptable base or carrier.
  • Exemplary but not exclusive formulations according to the present invention are formulations such as: 1) a formulation which is a suppository formulation in an acceptable suppository base; 2) a formulation which is an oral formulation (e.g. tablet, capsule or liquid); 2) a formulation which is a transmucosal delivery formulation; 3) a formulation which is a topical ophthalmic formulation (e.g. a liquid, semi-solid or implant) for reducing the intraocular pressure and/or inflammation in the treatment of glaucoma and/or eye inflammation uveitis in an acceptable ophthalmic carrier; 4) an external or internal depot delivery system for the eye (e.g.
  • topical ophthalmic formulations can be for example a formulation which is a polymeric ocular film using lipid Nano particles.
  • a further embodiment of the present invention is a formulation for administration of a biologically active CBD analog to a subject in need of treatment of a disease condition comprising a therapeutically effective amount of at least one compound of per formula I in an acceptable base or carrier.
  • the formulation for administration of a biologically active CBD analog to a subject in need of treatment of a disease condition comprising a therapeutically effective amount of at least one compound wherein the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate, CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate, CBD-Mono-Valinate-Mono-Hemisuccinate, or CBD-monovalinate-dihemisuccinate in an acceptable base or carrier.
  • the formulation can comprise a suppository formulation in an acceptable suppository base; an oral formulation; a transmucosal delivery formulation; a topical ophthalmic formulation; or an external or internal depot delivery system.
  • a still further embodiment of the present invention is a method of treating pain management comprising administering to a subject in need of such treatment an effective amount of at least one compound according formula I.
  • the compound used in the present method is at least one compound wherein the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate, CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate, CBD-Mono-Valinate-Mono-Hemisuccinate, or CBD-monovalinate-dihemisuccinate in an acceptable base or carrier.
  • the pain management can be, for example, pain management in oncology or neuropathic pain management.
  • the present invention relates to a method of blocking opiate additive properties and comprises administering to a subject in need of such treatment an effective amount of at least one compound per formula I.
  • the compound used in this method is at least one compound wherein the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate, CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate, CBD-Mono-Valinate-Mono-Hemisuccinate, or CBD-monovalinate-dihemisuccinate in an acceptable base or carrier.
  • the present invention can also encompass a method of preventing addiction to morphine because of extended morphine use comprising administering to a subject in need of such treatment an effective amount of at least one compound per formula I or preferably the compound used in this method is at least one compound wherein the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate, CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate, CBD-Mono-Valinate-Mono-Hemisuccinate, or CBD-monovalinate-dihemisuccinate in an acceptable base or carrier.
  • the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate, CBD-
  • FIG. 1 shows plasma levels of CBD vs time following rectal administration of 6.125 mg or 4.625 mg CBD-Val-HS in a lipophilic suppository (Wecobe W base).
  • FIG. 2 shows the plasma levels of CBD following the rectal administration of 7 mg CBD-Val-HS in a hydrophilic base (PEG 1000).
  • FIG. 3 shows plasma levels of CBD-Mono-VHS vs. time following rectal administration of 7.5 mg CBD-Mono-VHS in a lipophilic suppository (Wecobe W base).
  • FIG. 4 shows plasma levels of CBD-Mono-VHS vs. time following rectal administration of 7.5 mg CBD-Mono-VHS in a hydrophilic suppository (PEG 1000 base).
  • FIG. 5 shows plasma levels of CBD-Mono-VHS vs. time following oral administration of 4 mg CBD-Mono-VHS in sesame seed oil.
  • FIG. 6 a shows organ levels of CBD-Mono-VHS in 2 and 4 hr. post oral administration of 4 mg CBD-Mono-VHS.
  • FIG. 6 b shows plasma levels of CBD-Mono-VHS in 2 and 4 hr. post oral administration of 4 mg CBD-Mono-VHS.
  • FIG. 7 a shows concentration of CBD and THC vs. time post incubation of CBD at 37° C. at pH 1.2.
  • FIG. 7 b shows concentration of CBD vs. time post incubation of CBD at 37° C. at pH 7.4.
  • FIG. 8 shows concentration of CBD-Mono-VHS vs. time at pH's of 1.2 and 7.4.
  • FIG. 9 shows concentration of CBD-Di-VHS post incubation at 37° C. vs. time at pHs of 1.2 and 7.4.
  • FIG. 10 shows plasma levels of CBD vs. time following rectal administration of 7.5 mg CBD-HG in a lipophilic suppository (Wecobe W base).
  • FIGS. 11 a - d show organ levels of CBD and CBD-Mono-VHS 70 minutes after IP administration of two doses (30 and 60 ⁇ g) of CBD-Mono-VHS in mice: a) liver levels, b) spleen levels, c) kidney levels, and d) brain levels.
  • FIG. 12 shows plasma concentration of CBD-Mono-VHS 70 minutes after IP administration of two doses (30 and 60 ⁇ g) of CBD-Mono-VHS in mice.
  • CBD-Di-Glutaminate CBD-Di-Gln
  • CBD-Diglutaminate-Boc CBD-Di-Gln-Boc
  • CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring.
  • Boc-glutamine (2.2 eq.) was dissolved in DCM and 2.2 eq. of DCC was added to it while stirring.
  • CBD/DMAP solution was added to Boc-glutamine/DCC solution and allowed to stir for 30 minutes.
  • Thin layer chromatography (10% EtOAc/90% Hexane) indicated the completion of reaction. The product was purified using silica gel and product was eluted (in 90% EtOAc/10% Hexane) as pure compound.
  • CBD-di-Gln-boc was dissolved in THF while stirring.
  • HCl (g) was bubbled through it for approximately 3 minutes while stirring.
  • Excess HCl (g) was removed with N 2(g) and the solvent was evaporated. Product was confirmed by mass spectrometry.
  • CBD-Di-Hemisuccinate CBD-Di-HS.
  • CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (2.2 eq.) and triethylamine were added to CBD/DMAP solution. The reaction was stirred for 30 minutes. The product was purified using silica gel and eluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasing to 75% EtOAc/25% Hexane) as pure compound. Product was confirmed by mass spectrometry.
  • CBD-Di-Alaninate CBD-Di-Ala
  • CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring.
  • Boc-alanine (2.2 eq.) was dissolved in DCM and 2.2 eq. of DCC was added to it while stirring.
  • CBD/DMAP solution was added to Boc-alanine/DCC solution and allowed to stir for 30 minutes.
  • the product was purified using silica gel and product was eluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasing to 15% EtOAc/85% Hexane) as pure compound.
  • CBD-di-Ala-boc was dissolved in THF while stirring.
  • HCl (g) was bubbled through it for approximately 3 minutes while stirring. Excess HCl (g) was removed with N 2(g) and the solvent was evaporated to dryness. Product was confirmed by mass spectrometry.
  • CBD-Di-Alaninate-Di-Hemisuccinate CBD-Di-Ala-Di-HS.
  • CBD-Di-Ala was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (2.2 eq.) and triethylamine were added to CBD-Di-Ala/DMAP solution. The reaction was stirred overnight. The product was purified using silica gel and eluted (in a gradient beginning at 30% EtOAc/70% Hexane and increasing to 100% EtOAc/0% Hexane) as pure compound. Product was confirmed by mass spectrometry.
  • CBD-Di-Val Structure of CBD-Di-Valinate (CBD-Di-Val).
  • CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring.
  • Boc-valine (2.2 eq.) was dissolved in DCM and 2.2 eq. of DCC was added to it while stirring.
  • CBD/DMAP solution was added to Boc-valine/DCC solution and allowed to stir for 5 minutes.
  • Thin layer chromatography (10% EtOAc/90% Hexane) indicated the completion of reaction.
  • the product was purified using silica gel and product was eluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasing to 5% EtOAc/95% Hexane) as pure compound.
  • CBD-di-Val-boc was dissolved in THF while stirring.
  • HCl (g) was bubbled through it for approximately 3 minutes while stirring. Excess of HCl (g) was removed with N 2(g) . Product was confirmed by mass spectrometry.
  • CBD-Di-Valinate-Di-Hemisuccinate CBD-Di-Val-Di-HS.
  • CBD-Di-Val was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (2.2 eq.) and triethylamine were added to CBD-Di-Val/DMAP solution. The reaction was stirred overnight. The product was purified using silica gel and eluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasing to 80% EtOAc/20% Hexane) as pure compound. Product was confirmed by mass spectrometry.
  • CBD-Di-Hemiglutarate CBD-Di-HG
  • CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Glutaric anhydride (2.2 eq.) and triethylamine were added to CBD/DMAP solution. The reaction was stirred for 30 minutes. The product was purified using silica gel and eluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasing to 40% EtOAc/60% Hexane) as pure compound. Product was confirmed by mass spectrometry.
  • CBD-Mono-Val CBD-Mono-Val
  • CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring.
  • Boc-valine (1.1 eq.) was dissolved in DCM and 1.1 eq. of DCC was added to it while stirring.
  • CBD/DMAP solution was added to Boc-valine/DCC solution and allowed to stir for 5 minutes.
  • the product was purified using silica gel and product was eluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasing to 3% EtOAc/97% Hexane) as pure compound.
  • CBD-Mono-Val-boc was dissolved in THF while stirring.
  • HCl (g) was bubbled through it for approximately 2 minutes while stirring. Excess HCl (g) was removed with N 2(g) . Product was confirmed by mass spectrometry.
  • CBD-Mono-Valinate-Mono-Hemisuccinate CBD-Mono-Val-Mono-HS.
  • CBD-Mono-Val was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (1.1 eq.) and triethylamine were added to CBD-Mono-Val/DMAP solution. The reaction was stirred overnight. The product was purified using silica gel and eluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasing to 30% EtOAc/70% Hexane) as pure compound. Product was confirmed by mass spectrometry.
  • CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring.
  • Boc-valine (1.1 eq.) was dissolved in DCM and 1.1 eq. of DCC was added to it while stirring.
  • CBD/DMAP solution was added to Boc-valine/DCC solution and allowed to stir for 5 minutes.
  • the product was purified using silica gel and product was eluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasing to 3% EtOAc/97% Hexane) as pure compound.
  • CBD-Mono-Val-boc was dissolved in THF while stirring.
  • HCl (g) was bubbled through it for approximately 2 minutes while stirring. Excess HCl (g) was removed with N 2(g) . Product was confirmed by mass spectrometry.
  • CBD-Mono-Val was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (2.2 eq.) and triethylamine were added to CBD-Mono-Val/DMAP solution. The reaction was stirred overnight. The product was purified using silica gel and eluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasing to 30% EtOAc/70% Hexane) as pure compound. Product was confirmed by mass spectrometry.
  • Formulations 0.5% w/v CBD equivalent in Tocrisolve emulsion.
  • Tocrisolve composition W/O emulsion composed of a 1:4 ratio of soya oil/water that is emulsified with the block co-polymer Pluronic F68.
  • CBD- CBD- CBD- VAL- VAL-HS- VAL- VAL-HS MONO MONO CBD-HS HCI In (In (In terms (In terms (In terms (In terms terms terms CBD of CBD) of CBD) of CBD) of CBD) of CBD) of CBD) of CBD
  • Example 12 In Vivo Eye Tissue Levels of CBD and CBD Analogs 90 Min. After Topical Application of 50 ⁇ L of Formulations Containing the Equivalent of 250 ⁇ g of CBD in Tocrisolve® Emulsion
  • Conscious male New Zeland albino rabbits were used. The formulations were applied topically into the rabbits eyes (50 ⁇ L containing the equivalent of 250 ⁇ g CBD) in Tocrisolve® emulsion formulations as described in Example 11. The animals were sacrificed 90 min. after drug application and the eye tissues harvested for analysis.
  • Table 2 shows the tissue levels (ng/g) following administration of CBD, CBD-Val-HCl and CBD-Val-HS.
  • CBD-Val and CBD-Val-HS Ocular tissue concentrations of CBD, CBD-Val and CBD-Val-HS (ng/gm of tissue); 90 min post topical application of CBD (0.47%), CBD-Val-HCl (0.94%) or CBD-Val-HS (1.2%) in Tocrisolve ® emulsion (Dose: 250 ⁇ g CBD; 50 ⁇ L instilled volume) respectively. ND-below detection limit.
  • Example 13 In Vivo Eye Tissue Levels of CBD VS Other Analogs of CBD
  • Formulations Fifty microlitres of 0.5% w/v CBD in Tocrisolve emulsion (Dose: 0.25 mg)
  • CBD-VAL- HS-MONO 0.97% w/v in CBD-VAL-MONO CBD Tocrisolve 0.65% w/v in 0.53% CBD-HS emulsion Tocrisolve w/v in 0.81% w/v
  • CBD Analog CBD Conc. (ng/g (ng/g detected Conc. Conc. Conc.
  • CBD-Val-HS reached both retina choroid and the iris-ciliary bodies but showed no detectable levels of CBD.
  • CBD-mono-Val-HS was detected in high concentration in the aqueous humor, retina choroid and iris-ciliary bodies.
  • the CBD-mono-Val-HS showed high levels of Free CBD in the retina choroid and iris-ciliary bodies.
  • Example 14 Comparison of the CBD and CBD-Analog Levels in the Occular Tissues Following Topical Administration of the Two Biologically Active Analogs, Namely CBD-Di-Val-HS and CBD-Mono-Val-HS
  • This example is a repeat of the experiment performed under Example 13 to show results reproducibility.
  • Sample preparation Aqueous humor, Vitreous humor, Retina-Choroid and Iris-Ciliary bodies analysed for parent compound as well as CBD.
  • Formulations Fifty microlitres of 0.5% w/v Tocrisolve emulsion formulations (Dose: 0.25 mg)
  • CBD-VAL-HS-MONO 1.2% CBD-VAL-HS Set 2 Set 2 Analog CBD Analog CBD Concentration concentration Concentration concentration (ng/g of tissue) (ng/g of tissue) (ng/g of tissue) (ng/g of tissue) Aqueous 98.7 ⁇ 19.8 61.3 ⁇ 5.9 ND ND Humor Vitreous ND ND ND ND Humor Retina 519 ⁇ 476 503 ⁇ 373 142 ⁇ 76 ND Choroid Iris 422 ⁇ 197 585 ⁇ 103 ND* ND Ciliary Bodies Plasma ND ND ND ND *Only one of the animals showed 160 ng of CBD-Val-HS/g of tissue. The analog was below quantifiable levels in the other animals.
  • R1 and R2 are natural amino acid residues (e.g. CBD-di-Val) or a dicarboxylic acid (e.g. CBD-di-HS) esters or the ester of the amino acid amide with a dicarboxylic acid (e.g. CBD-di-Val-di-HS), penetration into the ocular tissues is not adequate.
  • R1 and R2 are natural amino acid residues (e.g. CBD-di-Val) or a dicarboxylic acid (e.g. CBD-di-HS) esters or the ester of the amino acid amide with a dicarboxylic acid (e.g. CBD-di-Val-di-HS)
  • Example 15 Bioavailability of CBD from Suppository Formulations Containing CBD-Di-Val-Di-HS (CBD-Val-HS)
  • CBD-Val-HS was formulated in both lipophilic (Wecobe W base) and hydrophilic (PEG 1000 base) suppository formulations. The formulations were administered to cannulated rats (100 mg suppository per rat) and blood samples were collected, centrifuged and the plasma separated for LC/MS/MS analysis. The amount of CBD in the plasma samples was quantified. The amount of CBD-Val-HS in the plasma samples was not quantified.
  • FIG. 1 shows the plasma levels of CBD vs. time following administration of 6.125 mg or 4.625 mg CBD-Val-HS in a lipophilic suppository (Wecobe W base).
  • FIG. 2 shows the plasma levels of CBD following the administration of 7 mg CBD-Val-HS in a hydrophilic base (PEG 1000).
  • CBD-Mono-Val-Mono-Hemisuccinate CBD-Mono-VHS
  • a Lipophilic Suppository Formulation Wecobee M
  • CBD-Mono-Val-Mono-HS was formulated in Wecobee M suppository base (a triglyceride lipophilic base) at 75 mg/mL of melted base. The study was carried out in a cannulated rat model. Three animals were administered 100 ⁇ l. each of the semisolid formulation for a rectal dose of 7.5 mg CBD-Mono-VHS. This is followed by collection of blood samples (250 ⁇ l.) at each data point (0, 0.25, 0.5, 1, 2, 4, 6, and 24 hr.). The blood was centrifuged and the plasma was used for LC-MS/MS analysis. The results are shown in Table 5 and FIG. 3 .
  • Example 17 Bioavailability of CBD-Mono-Val-Mono-Hemisuccinate (CBD-Mono-VHS) from a Hydrophilic Suppository Formulation (Polyethylene Glycol 1000, PEG 1000)
  • CBD-Mono-Val-Mono-HS was formulated in PEG 1000 suppository base (a hydrophilic suppository base) at 75 mg/mL of melted base. The study was carried out in a cannulated rat model. Three animals were administered 100 ⁇ l. each of the semisolid formulation for a rectal dose of 7.5 mg CBD-Mono-VHS. This is followed by collection of blood samples (250 ⁇ l.) at each data point (0, 0.25, 0.5, 1, 2, 4, 6, and 24 hr.). The blood was centrifuged and the plasma was used for LC-MS/MS analysis. The results are shown in Table 6 and FIG. 4 .
  • CBD-Mono-Val-Mono-Hemisuccinate CBD-Mono-VHS
  • CBD-Mono-VHS reaches the organs and especially the brain
  • two cannulated rats were administered same dose as those in Example 18.
  • One rat was sacrificed at 2 hr. after dosing and the other at 4 hr. after dosing and the organs were harvested (brain, liver, and spleen) as well as blood for analysis.
  • Table 8a shows the organ levels of CBD-Mono-VHS at 2 and 4 hrs. after oral dosing (4 mg/animal) while Table 8b shows the plasma levels.
  • FIGS. 6 a and 6 b The data are depicted in FIGS. 6 a and 6 b.
  • the plasma levels were consistent with the data from Example 18 and the organs showed high levels of the drug indicating effective bioavailability.
  • CBD-Mono-VHS Plasma levels at 2 and 4 hr. after oral dosing with 4 mg/animal of CBD-Mono-VHS.
  • CBD-Mono-Val-Mono-HS (Plasma) Time Conc. (ng/mL) 2 HR 285 4 HR 53
  • Example 20 Stability of CBD-Mono-Val-Mono-Hemisuccinate (CBD-Mono-VHS) in Simulated Gastric Juice and Intestinal Juice
  • CBD is known to convert, at least partially, to ⁇ 9 -THC (the psychoactive component of cannabis ) and to other cannabinoids under the acidic conditions of the stomach.
  • ⁇ 9 -THC the psychoactive component of cannabis
  • cannabinoids under the acidic conditions of the stomach.
  • CBD and CBD analogs were evaluated under acidic and alkaline conditions to simulate exposure to gastric and intestinal fluids. The procedure is outlined as follows:
  • FIGS. 7 a , 7 b , 18 , and 19 show the results.
  • CBD converts to ⁇ 9 -THC under acidic conditions while CBD analogs of this invention do not produce ⁇ 9 -THC.
  • CBD is partially converted to THC under the acidic conditions of the gastric juice, but stable under the physiologic pH of 7.4.
  • CBD-Mono-VHS is stable under both acidic (gastric juice) conditions and intestinal (pH 7.4) juice conditions.
  • CBD-DiVal-DiHS is stable under acidic juice conditions and the physiologic (pH 7.4) intestinal juice conditions.
  • Example 22 Plasma and Organ Concentrations of CBD and CBD-Mono-VHS Following IP Administration of CBD-Mono-VHS in Mice
  • CBD-Mono-VHS was administered intraperitoneally to mice at 2 doses (30 ⁇ g and 60 ⁇ g equivalent of CBD/mouse). Seventy minutes after dosing the animals (3 mice in each dose group), all animals were sacrificed. Blood, as well as organs (liver, spleen, kidney, and brain), were harvested for LC-MS/MS analysis of their content of both CBD and CBD-Mono-VHS.
  • Table 13 shows the total CBD-Mono-VHS content of each organ for each animal for both doses with average and standard deviation, while Table 14 shows the total CBD content. Also shown is the concentration of CBD-Mono-VHS in the plasma 70 minutes after dosing.
  • FIG. 11 a liver
  • FIG. 11 b pleen
  • FIG. 11 c kidney
  • FIG. 11 d brain
  • FIG. 12 plasma concentration (ng/mL)
  • CBD cannabidiol
  • a sub-analgesic dose of or morphine in a mouse model of cisplatin induced neuropathy.
  • Mice received 12 alternating days of 2.3 mg/kg cisplatin and Ringers solution IP.
  • mice Male C57BL/6 mice (25-30 g; Envigo; Indianapolis, Ind.) were housed 5 per polycarbonate tub with soft bedding in a temperature and humidity controlled vivarium. Mice were maintained under a 12-hour light/dark cycle with lights on at 06:00. Food and water were available ad libitum. Animals acclimated to the vivarium 1 week prior to experimental manipulations. All experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Mississippi (Protocols 13-017 and 15-022).
  • Cisplatin (Tocris; Ellisville, Mo.) was dissolved in 0.9% saline to yield dosages 2.3 mg/kg/ml. Lactated Ringer's solution (0.25 mL; Abbott laboratories; Chicago, Ill.) was used to hydrate mice to prevent kidney and liver damage associated with repeated cisplatin administration. Morphine sulfate (Research Biochemicals International; Natick, Mass.) was dissolved in 0.9% saline to yield dosages of 0.1 and 2.5 mg/kg/ml. CBD 1.0 and 2.0 mg/kg/mL (ELI Laboratories; Oxford, Miss.) solutions, dissolved in 5% ethanol, 5% Cremophor and injectable water. All test articles were administered intraperitoneally (IP).
  • IP intraperitoneally
  • mice received 6 IP injections of cisplatin (2.3 mg/kg/mL) on alternating days with lactated Ringer's solution on intervening days over a 12-day period. Baseline eVF measurements were taken prior to enrollment in the study to ensure balanced group assignments. To monitor the progression of tactile allodynia additional eVF measurements were taken on Ringers Day 3 and 6 prior to daily injections. On Ringers Day 6, eVF measurements revealed significantly lower paw withdrawal thresholds indicative of neuropathy. Drug efficacy screening was conducted 2 days later to minimize the potential effect that repeated eVF testing may have on our CIN endpoint. Mice were counterbalanced and assigned to drug groups. All test compounds were delivered IP 45 minutes prior to eVF testing.
  • FIG. 13 The effects of the various test articles on cisplatin-induced tactile allodynia are summarized in FIG. 13 .
  • Baseline eVF responses prior to and after cisplatin administration are shown as dashed lines.
  • All mice showed lower response thresholds indicative of tactile allodynia.
  • mice receiving 2.5 mg/kg morphine displayed a robust attenuation of tactile allodynia. This finding is consistent with the literature that opioid agonists produce analgesia in a wide variety of pain models including CIN (Guidon et al., 2012). Mice receiving 1.0 mg/kg CBD displayed a modest but significant attenuation of tactile allodynia. A higher dose of CBD was ineffective in the model. A sub-analgesic dose of morphine (0.1 mg/kg) did not further alter the anti-allodynic properties of 1.0 mg/kg CBD given alone. However, this sub-analgesic dose of morphine greatly enhanced the efficacy of 2.0 mg/kg CBD producing an effect equivalent to that of 2.5 mg/kg dose of morphine alone. Finally, the effective morphine dose of 2.5 mg/kg did not further potentiate the 2.0 mg/kg CBD. Collectively, these findings demonstrate that the modest efficacy of CBD can be greatly enhanced with sub-analgesic doses of an opioid agonist.
  • Example 24 Efficacy of CBD-Mono-VHS in a Cisplatin-Induced Tactile Allodynia Model
  • CBD-Mono-VHS morphine sulfate
  • ELI Laboratories Oxford, Miss.
  • 1.0 to 4.0 mg/kg/mL was dissolved in 5% ethanol, 5% Cremophor and injectable water and are dose-equivalent in terms of CBD equivalent.
  • the full doses of CBD-Mono-VHS were 1.6 to 6.4 mg/kg. All test articles were administered intraperitoneally (IP). All experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Mississippi (Protocol 15-022).
  • FIG. 14 Efficacy screening of these test articles on cisplatin-induced tactile allodynia are summarized in FIG. 14 .
  • Baseline eVF responses prior to and after cisplatin administration are shown as dashed lines.
  • All mice showed lower response thresholds indicative of tactile allodynia.
  • mice receiving 2.5 mg/kg morphine displayed a robust attenuation of tactile allodynia.
  • CBD-Mono-VHS produced a robust dose dependent attenuation of tactile allodynia equivalent to 2.5 mg/kg morphine at the 3.0 and 4.0 mg/kg doses. Further, this CBD-Mono-VHS dose response function shifted to the left by the addition of a sub-analgesic dose of morphine. This drug combination achieved a maximum effect at the 2.0 mg/kg CBD-Mono-VHS dose that was as efficacious as 2.5 mg/kg morphine alone.
  • Each chamber has two stimulus-distinct conditioning chambers (Black versus white colored walls and wire or mesh metal rod flooring; 16.75 ⁇ 12.70 cm) separated by a third central start chamber (7.25 ⁇ 12.70 cm; colored grey with a smooth solid floor). Guillotine doors permitted confinement/access to individual chambers.
  • Morphine Sulfate (Research Biomedical International; Natick, Mass.) was dissolved in 0.9% saline to yield a dosage of 2.5 mg/ml.
  • the CPP procedure consists of four phases: 1) a 15-min apparatus habituation trial, 2) a 15-min trial to establish baseline CPP scores, 3) six 45 min drug conditioning trials, and 4) a 15-min trial to establish post-conditioning CPP score.
  • animals were placed in the gray start chamber for a 5-minute adaption period. Following the adaption period the guillotine doors were lifted allowing access to the entire apparatus. The test apparatus was thoroughly cleaned with 70% ethanol solution after each trial.
  • Preference scores was calculated by taking subtracting post-conditioning and baseline CPP scores with positive values reflecting reward and negative values reflecting aversion.
  • the formulations of the present invention comprise a therapeutically effective amount of at least one biologically active cannabidiol analog composition of the formula wherein R1 is natural amino acid residue, and salts/derivatives thereof in an acceptable suppository base.
  • the biologically active cannabidiol analogs consist essentially of biologically active cannabidiol analogs disclosed hereinabove.
  • the suppository formulation of this invention can be suppository formulations in which the suppository base is a hydrophilic base or a lipophilic base.
  • the suppository formulation can advantageously comprise the suppository formulation base which is a hydrophilic base such as polyethylene glycol 1000.
  • the present invention also relates to a topical ophthalmic formulation biologically active cannabidiol analogs for reducing the intraocular pressure and/or inflammation in the treatment of glaucoma or eye inflammatory conditions, respectively.
  • the formulation comprises a therapeutically effective amount of the present biologically active cannabidiol analogs and salts thereof in acceptable ophthalmic carrier.
  • a further embodiment of the invention relates to a Transmucosal Delivery Hot Melt Extrusion (HME) Patch formulation for the treatment of any disease condition responsive to CBD.
  • the formulation comprises a therapeutically effective amount of at least one compound of the present biologically active cannabidiol analog compositions.
  • Suppository bases can be classified per their physical characteristics into two main categories and a third miscellaneous group: (a) fatty or oleaginous bases, (b) water-soluble or water-miscible bases, and (c) miscellaneous bases, generally combinations of lipophilic and hydrophilic substances.
  • fatty or oleaginous materials used in suppository bases are cocoa butter and many hydrogenated fatty acids of vegetable oils, such as palm kernel oil and cottonseed oil.
  • fat-based compounds containing combinations of glycerin with the higher-molecular-weight fatty acids, such as palmitic and stearic acids may be found in fatty bases.
  • Such compounds, such as glyceryl monostearate and glyceryl monopalmitate are examples of this type of agent.
  • the bases in many commercial products employ varied combinations of these types of materials to achieve the desired hardness under conditions of shipment and storage and the desired quality of submitting to the temperature of the body to release their medicaments.
  • bases are prepared with the fatty materials emulsified or with an emulsifying agent present to prompt emulsification when the suppository contacts the aqueous body fluids. These types of bases are arbitrarily placed in the third, or miscellaneous, group of bases.
  • Cocoa Butter, NF is defined as the fat obtained from the roasted seed of Theobroma cacao . At room temperature, it is a yellowish-white solid having a faint, agreeable chocolate-like odor. Chemically, it is a triglyceride (combination of glycerin and one or different fatty acids) primarily of oleopalmitostearin and oleodistearin.
  • bases in this category include commercial products such as Fattibase (triglycerides from palm, palm kernel, and coconut oils with self-emulsifying glyceryl monostearate and polyoxyl stearate), the Wecobee bases (triglycerides derived from coconut oil) and Witepsol bases (triglycerides of saturated fatty acids C12-C18 with varied portions of the corresponding partial glycerides).
  • Fattibase triglycerides from palm, palm kernel, and coconut oils with self-emulsifying glyceryl monostearate and polyoxyl stearate
  • Wecobee bases triglycerides derived from coconut oil
  • Witepsol bases triglycerides of saturated fatty acids C12-C18 with varied portions of the corresponding partial glycerides.
  • the main members of water-soluble and water-miscible suppository bases are glycerinated gelatin and polyethylene glycols.
  • Glycerinated gelatin suppositories may be prepared by dissolving granular gelatin (20%) in glycerin (70%) and adding water or a solution or suspension of the medication (10%).
  • Polyethylene glycols are polymers of ethylene oxide and water prepared to various chain lengths, molecular weights, and physical states. They are available in several molecular weight ranges, the most commonly used being polyethylene glycol 300, 400, 600, 1,000, 1,500, 1,540, 3,350, 4,000, 6,000, and 8,000. The numeric designations refer to the average molecular weight of each of the polymers. Polyethylene glycols having average molecular weights of 300, 400, and 600 are clear, colorless liquids. Those having average molecular weights of greater than 1,000 are wax like white solids whose hardness increases with an increase in the molecular weight. Melting ranges for the polyethylene glycols follow:
  • polyethylene glycols may be combined by fusion, using two or more of the various types to achieve a suppository base of the desired consistency and characteristics.
  • miscellaneous group of suppository bases are mixtures of oleaginous and water-soluble or water-miscible materials. These materials may be chemical or physical mixtures. Some are preformed emulsions, generally of the water-in-oil type, or they may be capable of dispersing in aqueous fluids.
  • polyoxyl 40 stearate a surface-active agent that is employed in several commercial suppository bases.
  • Polyoxyl 40 stearate is a mixture of the monostearate and distearate esters of mixed polyoxyethylene diols and the free glycols, the average polymer length being equivalent to about 40 oxyethylene units.
  • the substance is a white to light tan waxy solid that is water soluble.
  • suppository bases Its melting point is generally 39° C. to 45° C. (102° F. to 113° F.).
  • Other surface-active agents useful in the preparation of suppository bases also fall into this broad grouping. Mixtures of many fatty bases (including cocoa butter) with emulsifying agents capable of forming water-in-oil emulsions have been prepared. These bases hold water or aqueous solutions and are said to be hydrophilic.
  • the preferred suppository bases in the present invention are water soluble or water miscible bases.
  • the transmucosal device film or films (in the case of co-extrusion or layering) generally comprises at least one water-soluble, water-swellable or water-insoluble thermoplastic polymer.
  • the thermoplastic polymer used to prepare the HME film may include, but is not limited to polyethylene oxide (PolyOx®), polyvinylpyrrolidone (Kollidon®), hydroxypropyl cellulose (Klucel®), ethyl cellulose, methylcellulose, alkylcelluloses, veegums clays, alginates, PVP, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose (e.g., AvicelTM), polacrillin potassium (e.g., AmberliteTM), sodium alginate, corn starch, potato starch, pregelatinized starch, modified starch, cellulosic agents, montmorrilonite clays (e.g., bentonite), gums, agar, locust bean gum, gum karay
  • This matrix may optionally contain a bio adhesive (such as a Carbopol, polycarbophil, chitosan or others known to those skilled in the art—to further enhance the bio-adhesivity of the cannabinoid itself) or a bio adhesive layer may be laminated onto the matrix film or patch containing the cannabinoid.
  • a bio adhesive such as a Carbopol, polycarbophil, chitosan or others known to those skilled in the art—to further enhance the bio-adhesivity of the cannabinoid itself
  • an impermeable backing layer may be incorporated to insure unidirectional flow of the drug through the patient's mucosa.
  • a rate controlling film or membrane may also be laminated or sprayed onto the cannabinoid-containing matrix to further control the rate of release of the actives.
  • the transmucosal preparation will preferably contain a ‘penetration enhancer’ (which may also be referred to as an absorption enhancer or permeability enhancer).
  • penetration enhancers may include bile salts, such as sodium deoxycholate, sodium glycodeoxycholate, sodium taurocholate and sodium glycocholate, surfactants such as sodium lauryl sulfate, Polysorbate 80, laureth-9, benzalkonium chloride, cetylpyridinium chloride and polyoxyethylene monoalkyl ethers such as the BRIJ® and MYRJ® series.
  • Additional penetration enhancers for inclusion in the embodiment include benzoic acids, such as sodium salicylate and methoxy salicylate, fatty acids, such as lauric acid, oleic acid, undecanoic acid and methyl oleate, fatty alcohols, such as octanol and nonanol, laurocapram, the polyols, propylene glycol and glycerin, cyclodextrins, the sulfoxides, such as dimethyl sulfoxide and dodecyl methyl sulfoxide, the terpenes, such as menthol, thymol and limonene, urea, chitosan and other natural and synthetic polymers.
  • benzoic acids such as sodium salicylate and methoxy salicylate
  • fatty acids such as lauric acid, oleic acid, undecanoic acid and methyl oleate
  • fatty alcohols such as octanol and nonanol,
  • the hot-melt extruded or hot-melt molded matrix may also comprise as bio adhesives such as water-soluble or water-swellable polymers derived from acrylic acid or a pharmaceutically acceptable salt thereof, such as the polyacrylic acid polymers, including carbomers, polycarbophils and/or water-soluble salts of a co-polymer of methyl vinyl ether and maleic acid or anhydride (Gantrez MS-955).
  • bio adhesives such as water-soluble or water-swellable polymers derived from acrylic acid or a pharmaceutically acceptable salt thereof, such as the polyacrylic acid polymers, including carbomers, polycarbophils and/or water-soluble salts of a co-polymer of methyl vinyl ether and maleic acid or anhydride (Gantrez MS-955).
  • the transmucosal preparation can also comprise one or more pH-adjusting agents to improve stability and solubility.
  • the pH modifying agents can control cannabinoid release and enhance bio adhesion.
  • a pH-adjusting agent can include, by way of example and without limitation, an organic acid or base, an alpha-hydroxy acid, or a beta-hydroxy acid. Suitable agents include tartaric acid, citric acid, fumaric acid, succinic acid and others known to those of ordinary skill in the art.
  • the transmucosal preparation can also comprise one or more cross-linking agents to reduce matrix erosion time, control release of the cannabinoid or enhance bio adhesion.
  • a cross-linking agent can include, by way of example and without limitation, an organic acid, an alpha-hydroxy acid, or a beta-hemolytic-hydroxy acid. Suitable cross-linking agents include tartaric acid, citric acid, fumaric acid, succinic acid and others known to those of ordinary skill in the art.
  • the transmucosal preparation may also contain other components that modify the extrusion, molding or casting characteristics or physical properties of the matrix.
  • Such other components are well known to those of ordinary skill in the pharmaceutical sciences and include, for example, polyethylene, xylitol, sucrose, surface-active agents, others known to those skilled in the art, and combinations thereof.
  • the transmucosal preparation of the present invention can also include super-disintegrants or absorbents.
  • super-disintegrants or absorbents examples include sodium starch glycolate (ExplotabTM, PrimojelTM) and croscarmellose sodium (Ac-Di-Sol®).
  • absorbents include cross-linked PVP (PolyplasdoneTM XL 10), clays, alginates, corn starch, potato starch, pregelatinized starch, modified starch, cellulosic agents, montmorrilonite clays (bentonite), gums, agar, locust bean gum, gum karaya, pectin, tragacanth, and other disintegrants known to those of ordinary skill in the art.
  • the transmucosal preparation of the invention can include a chelating agent.
  • Suitable chelating agents include EDTA, polycarboxylic acids, polyamines, derivatives thereof, and others known to those of ordinary skill in the art.
  • the transmucosal preparation of the invention can include a surfactant.
  • Suitable surfactants include sucrose stearate, Vitamin E derivatives, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and others known to those of ordinary skill in the art.
  • the transmucosal preparation of the invention can include a preservative.
  • Preservatives include compounds used to prevent the growth of microorganisms. Suitable preservatives include, by way of example and without limitation, benzalkonium chloride, propyl paraben, methyl paraben, benzyl alcohol, cetylpridinium chloride, chlorobutanol, sorbic acid, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal and others known to those of ordinary skill in the art.
  • flavorant As used herein, the term “flavorant”, “flavor” or “fragrance” is intended to mean a compound used to impart a pleasant flavor and often odor to a pharmaceutical preparation, in addition to the natural flavorants, many synthetic flavorants are also used. Such compounds include, by way of example and without limitation, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin and others known to those of ordinary skill in the art. Flavors incorporated in the composition may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extract from plants, leaves, flowers, fruits and so forth and combinations thereof.
  • oils may include oil of wintergreen, clove oil, bay oil, anise oil, eucalyptus , thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.
  • useful as flavors are vanilla, citrus oils, including lemon, orange, lime and grapefruit, and fruit essences, including grape, apple, pear, peach, strawberry, raspberry, cherry, plum, apricot, and so forth.
  • Flavors that have been found to be particularly useful include commercially available orange, grape, cherry, and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on several factors, including the organoleptic effect desired.
  • colorant is intended to mean a compound used to impart color to solid pharmaceutical preparations.
  • Such compounds include, by way of example and without limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide red.
  • suitable colorants include titanium dioxide and natural coloring agents such as grape extract, beet red powder, carmine, turmeric, paprika, and others known to those of ordinary skill in the art.
  • the transmucosal preparation of the invention can include an antioxidant to prevent the deterioration of preparations by oxidation.
  • antioxidants include, by way of example and without limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), hypophophorous acid, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate and sodium metabisulfate and others known to those of ordinary skill in the art.
  • suitable antioxidants include, for example, vitamin C, sodium bisulfite, vitamin E and its derivatives, propyl gallate, a sulfite derivative, and others known to those of ordinary skill in the art.
  • the transmucosal preparation of the invention may contain a release rate modifier.
  • Suitable release rate modifiers include hydroxypropyl cellulose (HPC), poly (ethylene oxide) (PEO), hydroxypropyl methylcellulose (HPMC), ethyl cellulose, cellulosic polymers, acrylic polymers, fat, waxes, lipid, or a combination thereof, hi some embodiments, the release rate modifier is polycarbophil, carbomer or a polysaccharide.
  • the ingredients and chemicals used to produce the transmucosal preparation used in this invention are of acceptable quality, preferably pharmaceutically acceptable quality.
  • the biologically active cannabidiol analogs-containing transmucosal preparation is homogenous and pharmaceutically acceptable.
  • the transmucosal preparation of the invention can include stabilizers to protect against hydrolysis.
  • stabilizers may include cyclodextrins, chelating agents and surfactants.
  • the topical ophthalmic formulation can be solutions, emulsions, lipid nanoparticulate or matrix films. Other formulations known to one skilled in the art may also be used.
  • the lipid nanoparticulate, emulsions and matrix films are the most preferred formulations.
  • solubilizers typically will require solubilizers in view of the low solubility of the cannabinoids.
  • solubilizers that can be used in ophthalmic formulations include surfactants which form micellar solutions (since the active ingredient is entrapped in micelles) and complex forming agents or combinations thereof.
  • Commonly used surfactants in ophthalmic formulations include polyoxyethylene sorbates (e.g. Tween® 20 and Tween® 80), polyoxyl hydrogenated castor oils (e.g.
  • Cremphor® EL and Cremophor® RH 40 Cremphor® EL and Cremophor® RH 40
  • Tyloxapol® polyoxyethyelene ethers
  • Myrj® series alkoxylated fatty acid esters
  • sorbitan esters Span® series
  • Cyclodextrins such as hydroxypropyl betacyclodextrin and randomlymethylated beta cyclodextrins, are commonly used to enhance solubility through inclusion complex formation.
  • the solubilizers may be used alone or in combination.
  • Emulsions An emulsion is a system consisting of two immiscible liquid phases (oil and water), one of which is dispersed throughout the other as fine droplets, the system being stabilized by a third component, the emulsifying agent.
  • Emulsions are inherently unstable, and emulsifiers are essential for both their initial formation and long-term stability.
  • Emulsions may be oil in water (oil phase dispersed in the aqueous phase) or water in oil (water phase dispersed in the oil phase) emulsions.
  • oil in water in oil emulsions and water in oil in water emulsions are also known in the art.
  • the oil phase may consist of oils such as soyabean oil, castor oil, sesame oil and olive oil.
  • emulsion stabilizers or emulsifying agents are known in the art and include surfactants and phospholipids.
  • surfactant emulsifiers include polyoxyethylene sorbates (e.g. Tween® 20 and Tween® 80), polyoxyl hydrogenated castor oils (e.g. Cremphor® EL and Cremophor® RH 40), Tyloxapol®, polyoxyethyelene ethers (Brij® series) and alkoxylated fatty acid esters (Myrj® series), sorbitan esters (Span® series) and others know to a person skilled in the art.
  • phospholipids that may be used as emulsion stabilizers include phospholipids (e.g. phosphatidylcholine, phosphatidylinositol, phosphatidylglycerol).
  • Lipid nanoparticles Colloidal dispersions of solid lipid nanoparticles (SLNs) or nanostructured lipid carriers (NLCs) containing the therapeutic agent may also be used.
  • the drug is loaded in the lipid phase, which is then dispersed in the aqueous phase.
  • NLCs nanostructured lipid carriers
  • SLNs solid lipid nanoparticles
  • lipid phase which is then dispersed in the aqueous phase.
  • NLCs nanostructured lipid carriers
  • stabilizers such as surfactants and other components such as glycerine and propylene glycol may also be used alone and in combination thereof.
  • Matrix films prepared using melt-extrusion or melt-cast technology can also be used.
  • the films comprise a thermoplastic polymer as the carrier of the active ingredient.
  • the thermoplastic polymer used may include, but is not limited to polytheylene oxide (PolyOx®), polyvinylpyrrolidone (Kollidon®), hydroxypropyl cellulose (Klucel®), ethyl cellulose, methylcellulose, alkylcelluloses, veegums clays, alginates, PVP, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose (e.g., AvicelTM), polacrillin potassium (e.g., AmberliteTM), sodium alginate, corn starch, potato starch, pregelatinized starch, modified starch, cellulosic agents, montmorrilonite clays (e.g., bentonite), gums, agar, locust bean gum, gum karaya, pecitin, tragacanth, and
  • the matrix film may also comprise of bioadhesives such as water-soluble or water-swellable polymers derived from acrylic acid or a pharmaceutically acceptable salt thereof, such as the polyacrylic acid polymers, including carbomers, polycarbophils and/or water-soluble salts of a co-polymer of methyl vinyl ether and maleic acid or anhydride (Gantrez MS-955).
  • bioadhesives such as water-soluble or water-swellable polymers derived from acrylic acid or a pharmaceutically acceptable salt thereof, such as the polyacrylic acid polymers, including carbomers, polycarbophils and/or water-soluble salts of a co-polymer of methyl vinyl ether and maleic acid or anhydride (Gantrez MS-955).
  • the topical ophthalmic compositions may include additional or alternative polymeric ingredients and/or viscosity agents to increase stability and/or retention on the ocular surface.
  • additional or alternative polymeric ingredients and/or viscosity agents include carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer, xanthan gum, hyaluronic acid, any combinations thereof or the like.
  • buffering agents include citrate, borate and acetate buffers.
  • Tonicity adjusting agents may include for example sodium chloride and potassium chloride.
  • stabilizers e.g. antioxidants and chelating agents
  • penetration enhancers e.g. benzalkonium chloride, saponins, fatty acids, polyoxyethylene fatty ethers, alkyl esters of fatty acids, pyrrolidones, polyvinylpyrrolidone, pyruvic acids, pyroglutamic acids and their mixtures, among others, may also be included.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210030708A1 (en) * 2016-01-29 2021-02-04 University Of Mississippi Biologically Active Cannabidiol Analogs

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2530001B (en) 2014-06-17 2019-01-16 Gw Pharma Ltd Use of cannabidiol in the reduction of convulsive seizure frequency in treatment-resistant epilepsy
GB2531281A (en) 2014-10-14 2016-04-20 Gw Pharma Ltd Use of cannabidiol in the treatment of intractable epilepsy
WO2018096504A1 (en) * 2016-11-28 2018-05-31 Kalytera Therapeutics, Inc Cbd prodrugs, compositions, and methods of administering cbd and cbd prodrugs
CN107669744A (zh) * 2017-11-30 2018-02-09 云南汉木森生物科技有限责任公司 含有工业大麻的药包
CA3118895A1 (en) * 2018-11-07 2020-05-14 Columbia Care Llc Suppository formulations having cannabinoid
WO2021000053A1 (en) * 2019-07-04 2021-01-07 Canopy Growth Corporation Cannabinoid derivatives
JP7475731B2 (ja) * 2019-09-26 2024-04-30 ファーストライト ファーマシューティカルズ，エルエルシー カンナビノイドプロドラッグ化合物
EP3825354A1 (en) * 2019-11-25 2021-05-26 Largan Medical Co., Ltd. Plasticizer and plastic product
US11419800B2 (en) 2019-12-06 2022-08-23 JLABS Beauty LLC Topical compositions containing rose oil and cannabidiol and methods of making and using the same
US11396500B2 (en) * 2019-12-18 2022-07-26 Dieu Cam Vuong Heat and oxidation resistant Δ9 tetrahydrocannobinol (THC) and cannabiniol (CBD) compound and method of manufacturing the same
EP4088723A4 (en) * 2020-01-08 2024-02-21 Chengdu Baiyu Pharmaceutical Co Ltd CANNABIDIOL DERIVATIVE, METHOD FOR THE PRODUCTION THEREOF AND MEDICAL USE THEREOF
GB202002754D0 (en) 2020-02-27 2020-04-15 Gw Res Ltd Methods of treating tuberous sclerosis complex with cannabidiol and everolimus
WO2021184010A1 (en) * 2020-03-13 2021-09-16 Milane Michael Novel nano-formulation of cannabidiol (cbd) and other cannabinoids for treatment of ocular disorders
CA3179442A1 (en) 2020-05-22 2021-11-25 Brian Warrington Compositions for treating acne and dermatological conditions
WO2022111587A1 (zh) * 2020-11-25 2022-06-02 成都百裕制药股份有限公司 大麻素类化合物的制备方法
CN116253700A (zh) * 2021-12-10 2023-06-13 德义制药有限公司 一种大麻二酚衍生物及其制备方法和应用
CN116253671A (zh) * 2021-12-10 2023-06-13 德义制药有限公司 一种大麻二酚衍生物及其制备方法和应用
WO2023235386A1 (en) * 2022-05-31 2023-12-07 Trait Biosciences, Inc. Water-soluble cannabinoid prodrugs compositions and methods of synthesizing the same
CN116983264B (zh) * 2023-09-28 2023-12-22 中国农业科学院农产品加工研究所 一种二氢大麻二酚二苯甲酸酯的包埋体系及其制备方法和应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3728360A (en) 1971-08-31 1973-04-17 Little Inc A Ester derivatives of tetrahydrocannabinol
WO2008107879A1 (en) 2007-03-05 2008-09-12 Yissum Research Development Company Of The Hebrew University Of Jerusalem Novel cannabidiol derivatives and their use as anti-inflammatory agents
US20090036523A1 (en) * 2007-07-30 2009-02-05 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
WO2010051541A2 (en) 2008-10-31 2010-05-06 The University Of Mississippi Compositions containing delta-9-thc-amino acid esters and process of preparation
WO2011026144A1 (en) 2009-08-31 2011-03-03 Alltranz Inc. Use of cannabidiol prodrugs in topical and transdermal administration with microneedles
WO2014134127A1 (en) 2013-02-26 2014-09-04 Northeastern University Cannabinergic nitrate esters and related analogs
US20150218121A1 (en) 2007-11-30 2015-08-06 Zynerba Pharmaceuticals, Inc. Prodrugs of tetrahydrocannabinol, compositions comprising prodrugs of tetrahydrocannabinol and methods of using the same

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112018015570A2 (pt) 2016-01-29 2018-12-26 Univ Mississippi análogos de canabidiol biologicamente ativos
WO2017147202A1 (en) * 2016-02-22 2017-08-31 West Pharmaceutical Services, Inc. Drug delivery device state recognition
US20170298399A1 (en) * 2016-04-15 2017-10-19 Full Spectrum Laboratories Ltd Biosynthesis of cannabinoid prodrugs and their use as therapeutic agents
WO2017216362A1 (en) * 2016-06-16 2017-12-21 Full Spectrum Laboratories Ltd Methods for the manufacture of cannabinoid prodrugs, pharmaceutical formulations and their use
WO2018096504A1 (en) * 2016-11-28 2018-05-31 Kalytera Therapeutics, Inc Cbd prodrugs, compositions, and methods of administering cbd and cbd prodrugs

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3728360A (en) 1971-08-31 1973-04-17 Little Inc A Ester derivatives of tetrahydrocannabinol
WO2008107879A1 (en) 2007-03-05 2008-09-12 Yissum Research Development Company Of The Hebrew University Of Jerusalem Novel cannabidiol derivatives and their use as anti-inflammatory agents
US20090036523A1 (en) * 2007-07-30 2009-02-05 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
WO2009018389A1 (en) 2007-07-30 2009-02-05 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
US20150218121A1 (en) 2007-11-30 2015-08-06 Zynerba Pharmaceuticals, Inc. Prodrugs of tetrahydrocannabinol, compositions comprising prodrugs of tetrahydrocannabinol and methods of using the same
WO2010051541A2 (en) 2008-10-31 2010-05-06 The University Of Mississippi Compositions containing delta-9-thc-amino acid esters and process of preparation
US20150045282A1 (en) 2008-10-31 2015-02-12 The University Of Mississippi Compositions containing delta-9-thc-amino acid esters and process of preparation
WO2011026144A1 (en) 2009-08-31 2011-03-03 Alltranz Inc. Use of cannabidiol prodrugs in topical and transdermal administration with microneedles
WO2014134127A1 (en) 2013-02-26 2014-09-04 Northeastern University Cannabinergic nitrate esters and related analogs

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
A. Alexander et al., Cannabinoids in the treatment of cancer, Cancer Lett. (2009), doi:10.1016/j.canlet.2009.04.005.
Amptoulach S., Tsavaris N. Neurotoxicity caused by the treatment with platinum analogues. Chemotherapy Research and Practice. 2011; Article ID 843019.
Anderson, Chem & Biol (2003), vol. 10, pp. 787-797. (Year: 2003). *
Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annual Review of Neuroscience. 1984; 7:309-338.
Burnstein, Bioorganic & Med Chem (2015), vol. 23, pp. 1377-1385. (Year: 2015). *
Chiou LC, Hu SS, Ho Y. Targeting the cannabinoid system for pain relief? Act Anaesthesiologica Taiwanica. 2013; 51:161-170.
Cox ML, Haller VL, Welch SP. Synergy between Δ9-tetrahydrocannabinol and morphine in the arthritic rat. European Journal of Pharmacology. 2007; 567:125-130.
Examination Report No. 1 in the counterpart Australian Application No. 2017212651, dated Jan. 17, 2019.
First Examination Report in the counterpart New Zealand Application No. 745595, dated Feb. 20, 2019.
Guindon J., Lai Y., Takacs SM, Bradshaw HB, Hohmann AG. Alterations in endocannabionid tone following chemotherapy-induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment. Pharmacological Research. 2012; 67, 94-109.
Hall W., Christie M., Currow D. Cannabinoids and cancer: causation, remediation, and palliation. The Lancet. 2005; 6:35-42.
International Preliminary Report on Patentability in International Application No. PCT/US2017/015366, dated Aug. 9, 2018.
International Search Report in International Application No. PCT/US2017/015366, dated Apr. 12, 2017.
Khasabova IA, Khasabov S., Paz J., Rose C., Simone DA. Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. Neurobiology of Disease. 2012; 32, 7091-7101.
Kim JH, Dougherty PM, Abdi S. Basic science and clinical management of painful and non-painful chemotherapy-related neuropathy. Gynecologic Oncology. 2015; 136:453-459.
Mansour A., Khachaturian H., Lewis ME, Akil H, Watson SJ. Anatomy of CNS opioid receptors. Trends in Neuroscience. 1988; 11: 308-314.
Miltenburg NC, Booger W. Chemotherapy-induced neuropathy: a comprehensive survey. Cancer Treatment Reviews. 2014; 40:872-882.
Neelakantan H., Tallarida RJ, Reishcenbach ZW, Tuma RF, Ward SJ, Walker EA. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice. Behavioural Pharmacology. 2015; 26:304-314.
Paice JA. Chronic treatment-related pain in cancer survivors. Pain. 2010; 152:84-89.
Park HJ, Stokes JA, Pirie E., Skahen J., Shtaerman Y., Yaksh TL. Persistent hyperalgesia in the cisplatin-treated mouse as defined by threshold measures, the conditioned place preference paradigm, and the changes in dorsal root ganglia activated transcription factor 3: the effects of gabapentin, ketorolac, and entanercept. Anesthesia and Analgesia. 2013; 116:224-231.
Pisanti S., Picardi P., D'Alessandro A., Laezza C., Bifulco M. The endocannabinoid signaling system in cancer. Trends in Pharmacological Sciences. 2013; 34, 273-282.
Thiel, Nature Biotechnology (2004), vol. 22(5), pp. 513-519. (Year: 2004). *
Toth C., Au S. A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy. Pain. 2008; 138:657-666.
Vera G, Cabezos PA, {tilde over (M)}artin MI, Abalo R. Characterization of cannabinoid-induced relief of neuropathic pain in a rat model of cisplatin-induced neuropathy. Pharmacology, Biochemistry and Behavior. 2013; 105, 205-212.
Wilson-Poe AR, Pocius E, Herschbach M, Morgan MM. The periaqueductal gray contributes to bi-directional enhancement of antinociception between morphine and cannabinoids. Pharmacology, Biochemistry and Behavior. 2013; 103: 444-449.
Wolf S., Barton D., Kottschade L., Grothey A., Lopriniz C. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. European Journal of Cancer. 2008; 44:1507-1515.

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US11337951B2 (en) * 2016-01-29 2022-05-24 University Of Mississippi Biologically active cannabidiol analogs
US11337952B2 (en) * 2016-01-29 2022-05-24 University Of Mississippi Biologically active cannabidiol analogs
US11337950B2 (en) * 2016-01-29 2022-05-24 University Of Mississippi Biologically active cannabidiol analogs
US11344525B2 (en) * 2016-01-29 2022-05-31 University Of Mississippi Biologically active cannabidiol analogs
US11596617B2 (en) * 2016-01-29 2023-03-07 University Of Mississippi Biologically active cannabidiol analogs

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